tbuckley/cabot-search huggingface dataset:
P01.03.B A quantitative comparison of cognitive performance and patient-reported symptoms in preoperative lower-grade glioma patients from two Dutch Hospitals
Authors: V Belgers, W van Buijtene, E Butterbrod, J G Röttgering, L Douw, P C De Witt Hamer, G M Rutten, M Klein, W De Baene, M C M Kouwenhoven, K Gehring
Journal: Neuro-Oncology (2022)

Abstract Background Protocols for assessment of (neuro)psychological outcomes in lower-grade glioma patients vary between hospitals. This potentially complicates generalization of these outcomes. We compared standardized scores on tests of two frequently impaired cognitive domains (attention and executive functioning (EF)), and two relevant patient-reported outcomes (PROs; depression and fatigue) of two neuro-oncological hospitals that use different measurement instruments. Material and Methods Data were used from preoperative assessments of patients with (IDH-mut) WHO grade II/III glioma tested between 2007 and 2021 at Amsterdam UMC (AMS) or at Elisabeth-Tweesteden Hospital Tilburg (ETZ). AMS patients were referred for (neuro)psychological assessment based on physician and patient preference (paper and pencil tests), whereas all ETZ patients routinely undergo screening (computerized tests). To compare scores of the different attention and EF tests we converted patients’ performances to z-scores based on normative data. For cognitive performance, we compared scores of different cognitive flexibility tests (CST vs SAT), processing speed tests (SDC vs LDMT), and Stroop tests (Stroop I and Stroop III). PROs included the CES-D vs HADS-D and the CIS-fatigue vs MVI-general fatigue (AMS vs ETZ, resp.). Differences were tested using Fisher's, χ 2, and Mann-Whitney U tests. Results Assessments were done median 4 weeks (AMS, n=97, range 19-0 weeks) and 1 day (ETZ, n=106; range 14-0 days) preoperatively. Age, sex, tumor location and histology were comparable between cohorts (p&amp;gt;0.05), but the AMS cohort showed significantly more grade III tumors (36% vs 16%) and more awake surgeries (84% vs 46%). Z-scores measuring attention and EF (n=94 and n=95, AMS vs ETZ) were not significantly different (CST vs SAT, percentage with a disorder (z &amp;lt;-1.5SD) 15% vs 13%; SDC vs LDMT 13% vs 14%; Stroop I 11% vs 18%; Stroop III 13% vs 16% at AMS and ETZ, resp.). Percentages of patients with possible depression (CES-D≥16, n=88 and HADS-D≥8, n=106) did not differ significantly between hospitals (28% vs 26%), nor did percentages of patients with severe fatigue (CIS-fatigue≥35, n=88 and MVI-general fatigue (z &amp;lt;-1.5SD), n=38, 42% vs 24% at AMS and ETZ, resp.). Conclusion Standardized scores of glioma patients on cognitive domains (attention and EF) and PROs (depression and fatigue) did not differ between two centers with slightly different samples using different testing protocols. This cautiously suggests that study findings on cognitive functioning and symptoms could be generalized. For research purposes, conjoint use of pooled populations for outcome evaluation could be explored with different samples from other centers using different instruments.
PL02.2.A Microglia-specific disruption of sialic acid-Siglec-9/E interactions. A novel immunotherapy against glioblastoma?
Authors: P Schmassmann, J Roux, T A Martins, M Ritz, T Shekarian, M McDaid, H Läubli G Hutter
Journal: Neuro-Oncology (2022)

Abstract Background Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MdM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. Material and Methods We employed a CT-2A orthotopic GBM mouse model with MG specific (Sall1CreERT2 x Sigleceflox) and whole innate-compartment (Cx3cr1CreERT2 x Sigleceflox) spatio-temporal deletion of Siglece. We applied multi-color flow cytometry, transcriptomics and proteomics analysis to decipher the immune response upon Siglece knockout. Results TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p &amp;lt; 0.001). In the MG specific spatio-temporal deletion of Siglece (Sall1CreERT2 xSigleceflox), we observed high MG-proliferation upon Siglec-E knockout (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p &amp;lt; 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p &amp;lt; 0.001). By extending the Siglece knockout to the MdM compartment in our glioma mouse model (Cx3cr1CreERT2 x Sigleceflox) we observed a significantly prolonged survival in the Cx3cr1Cre+ population (21d in Cre- vs. 27d post-tumor injection in Cre+, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (30d post-tumor injection in Cre+ + anti-CD47). Unbiased proteomics analysis revealed increased antigen processing and presentation capabilities of Siglece knockout MdMs which was confirmed by ex-vivo OT-1 cross-presentation assays. This bridging of innate and adaptive responses with increased T cell priming upon MdM Siglece knockout was further promoted by addition of anti-PD1 antibody to the combined Siglece knockout and anti-CD47 treatment arm. Animals harboring CT-2A tumors, exhibited a sustained survival benefit under the triple therapy, with 23% of animals experiencing long-term remission, even after tumor re-challenge into the contra-lateral hemisphere. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with increased GBM-cell phagocytosis by MG and MdMs and less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003). Conclusion These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.
OS06.5.A Investigating safety and efficacy of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma - the PriCoTTF phase I/II trial
Authors: S Kebir, L Lazaridis, T Schmidt, C Oster, J Feldheim, M Glas, D Pierscianek, M Proescholdt, P Hau, A Grosu, D Krex, B Scheffler, C Kleinschnitz, C Pöttgen, M Stuschke
Journal: Neuro-Oncology (2022)

Abstract Background The EF-14 phase III trial demonstrated improved survival for patients with newly diagnosed glioblastoma (nGBM) when TTFields therapy was added to adjuvant temozolomide chemotherapy. TTFields at 200 kHz are applied to the tumor utilizing arrays on the patients’ scalp. In preclinical studies, a synergistic inhibiting effect on glioblastoma cell proliferation was found for the combination of TTFields and radiotherapy. Based on these findings, we conduct the phase I/II PriCoTTF trial in adult nGBM patients to investigate the safety and efficacy of TTFields therapy initiated prior and concomitant to radiochemotherapy. Material and Methods Per study protocol, TTFields therapy is initiated following surgery and completed wound healing. Continuing throughout radiochemotherapy and adjuvant chemotherapy, TTFields therapy is used for approximately 9 months in total with TTFields rechallenge allowed at recurrence. Radiotherapy is conducted with arrays applied on the patients’ scalp. A total recruitment of 33 patients was sought, with 20 patients in arm A receiving normo-fractionated radiotherapy, and 13 elderly patients in arm B receiving hypo-fractionated radiotherapy. Safety and tolerance are the study’s primary endpoint, analyzed by a selection of pre-specified treatment-limiting toxicities (TLTs). Results A total of 33 patients have been enrolled. Patients' characteristics were mostly typical for glioblastoma, except for a rather low fraction of patients with gross total resection (GTR, 22.5%). The distribution of adverse events of common toxicity criteria (CTC) grade 3 or higher was comparable to that of established glioblastoma trials. Notably, skin toxicity of CTC grade 3 or higher was quite uncommon (n=2, 6%). As no patient developed TLTs, the study's primary endpoint was met. Median TTFields treatment duration was 8.4 months. Overall survival data was not mature enough (event rate 48%) to allow for a definite conclusion. Notably, on multivariable Cox regression, the number of days with TTFields adherence of more than 23 hours was independently associated with overall survival (HR 0.96, 95% confidence interval 0.93 - 0.99, p=0.008). Conclusion The PriCoTTF trial met its primary endpoint indicating that combined TTFields and radiotherapy is safe and well tolerated. High-grade skin toxicity was quite uncommon and the patients with high TTFields adherence seem to perform particularly well. An extended follow-up is required to provide first estimates regarding putative efficacy. At that point in time, the reduced overall TTFields duration and fraction of patients with GTR need to be factored in.
OS08.2.A Three layers of neuronal-like mechanisms driving brain tumor invasion
Authors: V Venkataramani, W Wick, T Kuner, F Winkler
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma are characterized by their infiltration into the whole brain. Membrane protrusions of glioma cells called tumor microtubes are subcellular structures contributing to glioma cell invasion. They are the anatomical building block to build a functional and therapy-resistant tumor cell network interconnected by tumor microtubes (TMs) that characterizes a glioblastoma cell subpopulation, while other subpopulations appear unconnected to other glioma cells. The biological role of glioblastoma cells lacking connections with each other remains unclear. Furthermore, how neurogliomal synapses influence this subpopulation is unclear. Material and Methods Time-lapse in vivo two-photon microscopy and single-cell RNA-sequencing are combined to characterize functional different subpopulations of glioblastoma cells. Intravital, augmented microscopy, three-dimensional calcium imaging, electrophysiology and volume electron microscopy are used to investigate the role of neuronal invasion mechanisms and the role of neurogliomal synapses for tumor microtube generation and dynamics. Results In-vivo imaging revealed that glioblastoma cells lacking connections to other tumor cells and astrocytes were the main subpopulation driving glioblastoma invasion invasion. These glioblastoma cells were characterised with single-cell RNA-sequencing. This revealed that this subpopulation is enriched for neuronal, neural progenitor-like, and non-mesenchymal-like cell states as previously described. Sparse regions enriched with such tumor-cell and astrocyte-unconnected, invasive glioblastoma cells evolve over time into regions with tumor-cell and astrocyte-connected, glioblastoma cell networks reflected by molecular cell state changes that are reflected in cell state changes in different regions of human glioblastoma. In addition, mechanisms of glioblastoma cell invasion resembled neuronal and neural progenitor patterns during brain development. Lastly, neuronal activity stimulated neurogliomal synapses and subsequently increased glioblastoma cell invasivieness by stimulating generation of new tumor microtubes and enhanced tumor microtube dynamics. Conclusion This study uncovers three novel layers of neuronal features driving glioblastoma cell invasion. We are able to connect molecular, cellular heterogeneity and functional glioblastoma cell states interlinking heterogeneity and dissemination of glioblastoma, two important hallmarks of this disease. Lastly, this study delineates a potential roadmap to clinical translation with the multidimensional characterisation of human glioblastoma.
P01.13.A The effect of musicality on language recovery after awake glioma surgery
Authors: P R Kappen, J van den Brink, J Jeekel, C M F Dirven, M Klimek, M Kamphuis, C S Docter-Kerkhof, S A Mooijman, R D S Nandoe Tewarie, M L D Broekman, A J P E Vincent, D Satoer
Journal: Neuro-Oncology (2022)

Abstract Background Awake craniotomy is used to resect tumor while preserving language. However, differences between patients in post-operative speech/language outcome are observed despite careful intra-operative monitoring. Literature describes improved performance in language tasks during cognitive tests in musicians. Moreover increased white matter connectivity properties in the corpus callosum are described in musicians compared to non-musicians. We hypothesize better recovery of language in musical patients after awake glioma surgery, caused by higher connectivity properties from the corpus callosum. Material and Methods Adult patients undergoing resection for glioma with an awake resection procedure at two neurosurgical centers were prospectively included. Patients without standardized language tests at pre- and post-operative level, with a glioblastoma multiforme (WHO grade 4) or undergoing re-resection were excluded. Language was assessed with the Diagnostic Instrument for Mild Aphasia (DIMA) and corrected for age and education years from a healthy population. The patients’ musical skill was assessed through questionnaires, and divided in groups based on the Musical Expertise Criterion (MEC) which defines musicality based the duration and intensity of musical training. Volumetric measures of the corpus callosum, corrected for total brain volumes, was calculated of each included patient based on the pre-operative structural MRI. Results Forty-six patients, enrolled between June 2015 and September 2019, were followed-up (mean/SD; 240/174 days after craniotomy) and divided in: non-musician (41.3%, n = 19), amateur-musician (34.8%, n=16) and trained-musician (23.9%, n = 11). Overall a decrease in language was observed after craniotomy (mean/SD) of -0.361/0.771. Musical abilities correlated with less decrease in language (mean/SD) when comparing non-musicians (-0.543/0.683) to amateur (-0.272/0.910) and trained (-0.176/0.693) musicians. An increased but non-significant trend (p=0.28) between musicality and corpus callosum / brain ratio (mean/SD) was observed in non-musicians (0.763, 0.718;0.808), amateur musicians (0.792, 0.745;0.838) and trained musicians (0.835, 0.778;0.891). Conclusion Musicality seemed to improve language outcome after awake glioma surgery, possibly attributed due to a higher white matter connectivity in the corpus callosum. Future studies with larger sample sizes are needed to confirm our findings.
P02.05.B Targeted therapies of Glioblastoma using single cell sequencing and drug-response analysis in a phase 2 clinical trial setting
Authors: M Lü, J Hendriksen, T Urup, P Hamerlik, K Wennerberg, U Lassen, H Skovgaard, J Weischenfeldt
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma is an aggressive brain tumour with a median survival of less than 15 months despite aggressive standard treatment consisting of neurosurgery, radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. There is no standard treatment at recurrence, and all have limited efficacy. In this study we will enroll glioblastoma patients from the Danish clinical trial “Protarget” to get a better understanding of resistance mechanisms and vulnerabilities in glioblastoma to give personalized medicine to glioblastoma patients at recurrent disease. We hypothesise that two connected factors are responsible for the failure to successfully target glioblastoma: i) intra-tumour heterogeneity and within this ii) cancer stem cells. Material and Methods We will use tumour tissue from glioblastoma patients included in the Danish phase 2, prospective, non-randomized clinical trial “Protarget” to establish short-term cultured neurospheres to preserve the heterogeneity of the tumour including cancer stem cells. We will then perform single cell RNA sequencing before and after drug screening. This setup will allow for a new approach to identify drug vulnerabilities at the single cell level. If successful in identifying drugs that leads to a clinical response, according to the "ProTarget" guidelines, we will consider scaling up the effort, to allow broader evaluation of efficacy. Our plan is to enroll 10 patients as a start. Patients will be selected based on ProTarget inclusion criteria and molecular profiling. We will further select patients with the following characteristics:1. IDH wildtype 2. High tumour purity (&amp;gt;50%). 3. High degree of intra-tumour heterogeneity. Results Enrollment for "Protarget" began in 2020 and our cohort will be part of this study, which is why enrollment has already started, but the first patient has not been enrolled yet. Clinical trial registry number for "Protarget" is NCT04341181. Conclusion This new and flexible approach to identify drug vulnerabilities at the single cell level in glioblastoma in order to find targeted therapies is a promising tool for future treatment of glioblastoma patients.
OS10.5.A Modeling immunocompetent tumor microenvironment in glioblastoma patient-derived orthotopic xenografts
Authors: P M Moreno-Sanchez, A Oudin, Y A Yabo, E Klein, V Baus, A Poli, A Michelucci, S P Niclou, A Golebiewska
Journal: Neuro-Oncology (2022)

Abstract Background To date, glioblastoma (GBM) remains a fatal disease, with a median overall survival of roughly over a year. There is a crucial need of new treatment options, yet most clinical trials have failed partly due to the lack of predictive preclinical model systems. Currently, most patient-derived preclinical models suffer from the reduction or absence of immune system components, which represents a bottleneck for adequate immunotherapy testing. Humanized mice offer new opportunities here, since they rebuild an adaptive human immune system in a NSG mouse. Derivation of glioblastoma patient-derived orthotopic xenografts (PDOXs) in humanized mice appears thus as a promising tool for testing new treatment strategies targeting the tumor microenvironment (TME). Material and Methods We derived PDOXs through intracranial implantation of GBM primary organoids in different immunocompromised mouse strains (Nude, NOD/SCID, NSG). To introduce back the adaptive human immune system, GBM PDOXs were further derived in human CD34+ hematopoietic stem cell-engrafted NSG (HU-CD34+) mice. We applied single-cell RNA-sequencing, multicolor flow cytometry, immunohistochemical analyses and functional studies to examine the heterogeneous TME in a cohort of GBM PDOX models. We further interrogated the contribution and crosstalk between the human and mouse components constituting the brain TME in HU-CD34+ PDOXs. Results We show that glioma PDOXs can be derived in mice of different background including Nude, NOD-SCID, NSG and HU-CD34+ mice. Mouse-derived TME created in PDOX models contains tumor-associated macrophages (TAMs) known as major immuno-suppressive components of human GBM tumors. We further show that PDOXs derived in HU-CD34+ NSG mice present human CD45+ immune cells in the bone marrow and blood. Interestingly, we detect an influx of human immune cells in tumors developed in the mouse brain, which interact with the brain-derived immunosuppressive TME of mouse origin. Conclusion We here provide a thorough characterization of the heterogeneous brain TME created in GBM PDOX models. We show that human GBM can instruct mouse-derived brain cells towards immune-suppressive TME. The missing adaptive immune component can be introduced by derivation of GBM PDOXs in humanized mice. Such immunocompetent in vivo models will be important for testing novel therapies targeting different immune components in GBM.
P02.01.B The telomere maintenance mechanism spectrum and its dynamics in gliomas
Authors: S Kim, T Chowdhury, H Yu, S Choi, K Kim, H Kang, J Lee, S Lee, J Won, K Kim, K Kim, M Kim, J Lee, J Kim, Y Kim, T Kim, S Choi, J Phi, Y Shin, J Ku, S Lee, H Yun, H Lee, D Kim, K Kim, J K Hur, S Park, S Kim, C Park
Journal: Neuro-Oncology (2022)

Abstract The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation indicates alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues. Here, we show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined in the dichotomy of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation and ATRX mutation. Moreover, we observed that a considerable proportion of gliomas lack both telomerase activity and ALT (Neither group). And this Neither group exhibited evidence of slow growth potential. From a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed but changes with glioma progression. Collectively, these results suggest that the TMM is a dynamic entity and that reflects the plasticity of the oncogenic biological status of tumor cells and that the TMM should be defined by the direct measurement of telomerase enzyme activity and evidence of ALT.
P03.10.B A successful case of Histiocytic sarcoma
Authors: E Bonzano, S Colombo, L Mantovani, R Di Liberto, A Filippi
Journal: Neuro-Oncology (2022)

Abstract Background Histiocytic sarcoma (HS) is an extremely rare malignant neoplasm accounting for less than 1% of all hemato-lymphoid neoplasms. Sixty percent of all cases are metastatic at presentation and the prognosis is really poor. Currently, there are limited treatment options for HS, and no standard treatment can be recommended. Surgery and/or chemotherapy are the most commonly employed treatment modalities for HS, while radiotherapy seems to be an effective option in patients with localized lesions. Material and Methods A 48-year-old woman admitted to our hospital for a drug-resistant neck pain. Her medical record review was relevant for hypothyroidism in replacement therapy, hystero-adnexectomy for fibromatosis (2 years ago), anxiety-depressive syndrome. A Brain and Head-and-Neck Magnetic Resonance Imaging (MRI) showed a left expansive osteolytic occipito-cervical vertebral lesion at level C1-C2, measuring 3.4cm x 2.3 cm x 2.6 cm. The mass was completely resected on July 12,2021 and pathological and immunohistochemical staining confirmed the diagnosis of HS with positive immunohistochemistry for CD163, CD4, CD68, CD14, CD45 / LCA; weak expression of S100 and focal positivity for lysozyme; Ki67 = 45%.On August 10, 2021 a 18F-FDG PET/CT imaging of the total body did not reveal any distal metastases. On August 13, 2021 a bone marrow aspirate showed no neoplastic cells. She underwent to an adjuvant chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE). On August 28,2021 a concomitant radiotherapy is given, with a total dose of 45 Gy delivered in 15 fractions plus a sequential boost to 54 Gy.Results: VMAT was used to deliver a conformal RT plan. The patient tolerated the entire treatment very well, with a Grade 1 dysphagia immediately after the completion of radiotherapy, with a complete resolution about a week later. At last Brain Head-and-Neck RMN and 18F-FDG PET/CT on March 28, 2022 there is no evidence of recurrent disease. Conclusion The favorable outcome of our patient with combined chemotherapy and radiotherapy should promote future research to explore treatment protocols in patients with localized or favorable subtypes of HS.For patients with a good PS, young age, long life expectancy, advanced RT techniques may be used to customize safe treatment.